Abstract 3277: In vivo CRISPR screening identifies PTDSS1 as a potential combinatorial target to improve immune checkpoint therapy response

Abstract Immune checkpoint therapy (ICT) has recently revolutionized the treatment paradigm for various types of cancer. However, despite the unprecedented safety and efficacy profile compared to traditional treatment options, many patients do not respond to ICT, highlighting the urgent need for novel strategies to improve ICT efficacy. Here, we used a pooled in vivo CRISPR knockout screening in a mouse bladder cancer model treated with immune checkpoint inhibitor to discover targets that may improve immunotherapy response. Our data identified Ptdss1, which encodes phosphatidylserine synthase 1, as a potential regulator of anti-PD-1 response. Depletion of Ptdss1 not only increased tumor cell immunogenicity and response to interferon gamma, but also facilitated development of an anti-tumor microenvironment. Ptdss1 depletion in tumor cells increased effector CD8+ T cells cytolytic function, decreased regulatory T cells activation and inhibitory function, increased frequency of iNOS+ myeloid cells and induced macrophage M2-to-M1 polarization. Ptdss1 knockdown induced changes in the tumor microenvironment were further amplified when combined with anti-PD-1 treatment, which translates into better tumor control and prolonged animal survival in mouse bladder cancer model. Together, our results provide insights on a new therapeutic strategy for overcoming resistance to immune checkpoint therapy through combination of PTDSS1 inhibition and PD-1 blockade. Citation Format: Jielin Liu, Swetha Anandhan, Sreyashi Basu, Yulong Chen, Sangeeta Goswami, Ashwat Nagarajan, Shelley Herbrich, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma. In vivo CRISPR screening identifies PTDSS1 as a potential combinatorial target to improve immune checkpoint therapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3277.